As a junior faculty member at Columbia University, my academic efforts focus on the study of frontotemporal dementia (FTD), a group of common dementing syndromes which presents with personality change, depression, alcoholism, psychosis, and parkinsonism. I plan to pursue as part of my MCSDA proposal, an observation I made when studying a family with 13 members affected with an autosomal dominant FTD-parkinsonian disorder (disinhibition-dementia-parkinsonism-amyotrophy complex). I mapped the disorder to chromosome 17q21-22. Subsequent analysis identified additional FTD-parkinson families linked to 17q21-22. My collaborators and I have narrowed the region bearing the locus for these dementia approximately 0.5 cM by meiotic recombination. My goal is to clone the disease gene and, under my sponsor's guidance, apply the following strategies; 1) to further refine the genetic interval harboring the 17qFTD locus through the use of a dense set of microsattelite markers to delineate the meiotic break point boundaries. My collaborators and I will physically clone the minimum genetic region using known chromosomal 17 yeast artificial chromosomes to isolate PI artificial chromosomes (PAC), bacterial artificial chromosomes and cosmids. 2) to identify expressed sequence tags (ESTs) and genes from genome databases to map them onto the available contig and isolate novel ESTs and genes by using the PACs in exon trapping and cDNA selection studies. 3)to I will search for genetic mutations in cDNA and genomic DNA. All of the necessary molecular techniques are currently available to me or my collaborators. Should my application be approved, I would anticipate success in my endeavor within the award period. A MCSDA three year award will provide me with the support I need to learn the methods of molecular genetics, and to acquire the necessary expertise and materials to provide the basis for future independent investigator (K02 or R29) awards.